Process for monoenolesterification at the 20-position of 11, 20-allopregnanediones



England, assignors to Glaxo Laboratories Limited, Greentord, England, a British company No Drawing. Application June 15, 1953, Serial-No, 361,842

a s p o y, pr c fiqn Grs Br tt? Au st 1.95

9 Claims. (Cl. 260397.45)

This invention is concerned with improvements in or relating to the monoenolesterification of 11:20-steroid diketones to provide 11-keto-2O1enol ester steroids. Such compounds are useful in the synthesis of cortisone and related substances in that the C17 side-chain (of the enol esters) is capable of conversion by way of a 17:20-oxide to a 17-hydroxy-20-keto compound as described for example in the case of certain compounds of the allo series in copending application Serial No. 361,814.

Certain work concerning the elaboration of the typical cortisone side-chain from ll:20-.diketones has been described using steroids of the pregnane series (in which the rings A'and B have a cis relationship). We have observed certain unexpected anomalies while attempting to apply the methods hitherto described for the elabora: tion of the cortisone side-chain in the pregnane series to the analogous compounds in the allo pregnane series. Thus Kritchevsky et al. (J. A. C. S. 1952, 74, 483) have described the conversion of a:hydroxy-11:20-diketopregnane to the corresponding l1g20-dienolacetate which on oxidation with perbenzoic acid yielded the 17:20- monoxide. These workers established that the 9:11- double bond in the dienolacetate was not attacked by the peracid, enabling the 11-lteto group to be regenerated. In our researches into the corresponding allo compounds we have established that the 11:;2 -dienolesters when oxidised with peracids yield a mixture of the 9:11-oxide, the 17:20-oxide and the 9211,17z20-dioxide in (very approximately) equal proportions. This fact renders the stated series of reactions described by Kritchevsky et al. practically valueless in the allo series.

We have now found a new and improved method of converting 11:20-steroid diketones into the correspond? ing 11-keto-.20 -enol esters in improved yield. In both the normal and the allo series our new process gives rise only to the monoenol esters; however, in general we prefer to apply this process to steroids of the allo series. The new process enables the desired 17-hydroxy+1l:20 diketones to be prepared in greater overall yield than by the process described by Kritchevsky et al. (loc cit). it should be noted that in order to compare yields, it is convenient to determine the overall yield of 17-hydroxy- 11:20-diketones from the corresponding 11:20-.diketones as the intermediate enol esters and epoxides are not so easily isolated.

Our new process for the preparation of the said enol esters is based upon treatment of the 11:20-diketones with a carboxylic acid anhydride in the presence of perchloric acid and a suitable solvent.

In order to explain our new process it is convenient to refer to the probable theoretical explanation thereof although it should be understood that such explanation is given only for the purposes of illustration without the invention being limited thereby.

We believe that in the reaction according to the invention the enol esterification involves initial attack by ited States Patent '0 2,751,398 Patented June 19, 1956 2 an acylium ion upon the 20-keto group to give an intermediate carbonium ion which by loss of a proton yields the desired ester. 2

This reaction may be schematically represented as follows:

( n. he rmula the rings A a d B r t ed fro h tru tu f rm la in rder to s m f xp n i he r u s derive m the c anh d d R 0 m- P QYQ in he P o ess) b lie e. at y emp y n a so nt ch educes the solvating power and the dielectric constant of the medium, the lifetime of the intermediate carbonium ion may be minimised and thus the chance of side reactions taking place is reduced.

In view of the foregoing, we employ in our process a solvent (hereinafter termed a suitable solven which has a dielectric constant substantially less than that of the acid anhydride employed and is unable to act as a Lewis base for acylium ions. Such solvents comprise particularly the halogenated hydrocarbons, we prefer to smel er hs s sratsd h r rbon t as low a dielectric, eoristant as possible, for example carbon tetrachloride.

According to the invention therefore, we provide a process for the monoenolesterification at the 20 position of- 1 1 20-steroid diketones in which the said diketones are reacted with a carboxylic acid anhydride in the presence of perchloric acid and a Suitable solvent as herein defined.

According to a feature of the invention, 11 :20-allosteroid dilgetones are used as the starting materials.

According to a further feature of the invention the acid anhydrides employed in the process are aliphatic anhydrides containing 4 to 10 carbon atoms. We prefer acetic anhydride.

The reaction may be carried out at various temperatures dependent on the nature of the suitable solvent but general a temperature within the range of from 20 to C. will be found convenient. Using perchloric acid as catalyst and carbon tetrachloride as solvent a temperature of 20 C. is preferable. We find further that from 0.1 to 20% of perchloric acid catalyst is in general suitable. We prefer also that the suitable solvent should represent from 50-95% of the total solvent medium. We prefer to employ at least 1.5 mols of acid anhydride per rnol of steriod starting material (in the case where the 3zposition is occupied by a hydroxy group 2.5 mols of anhydride will be required). a

The optimal temperature, concentration of catalyst and acetic anhydride, may be readily determined by experiment and for this purpose it is convenient to follow the reaction polarimetrically, since on enol esterification the specific rotation of the solution becomes less positive and it is possible by this means to obtain a rough guide to the rate and efiiciency of the reaction. It is not, however, convenient to isolate the enol ester and a more ac.- curate evaluation of the yield may be obtained by conversion of the product to the l7u hydroxy compound by way of the 17 :20-epoxide, as described for example in copending application Serial No. 361,814.

The reaction may be carried out either under homogeneous or heterogeneous conditions as demonstrated in Example 2 hereof.

For the preparation of cortisone intermediates the process according to the invention may for example be applied to compounds of the general formula CHs gj oit H II.

where R is an Organic radical derived from a carboxylic acid anhydride R20 and R is an esterified hydroxy group. We prefer such compounds in which R is an alkylacyl group containing from 25 carbon atoms. We also prefer that R should be an acyloxy group, for example an acetoxy, propionyloxy or benzoyloxy group.

For the better understanding of the invention we give by way of example the characteristics of one of the new compounds according to the invention:

3,8220 diacetoxy 11 ketaallopregn 17(20) ene [M. P. 15-15. [0111): +6.5 (chloroform).]

These characteristics were of course determined for the purest sample of the product we have been able to obtain and will be liable to variation according to the purity of any particular sample of the compound.

Although the process according to the invention is the best known to us for the production of the said new compounds, they may also be prepared from compounds of Formula I above under other enolesterifying conditions, that is without the suitable solvents herein referred to.

In carrying out the process without such suitable solvents the conditions of the esterification to be employed so that only the 20-keto group is attacked must be selected by means of preliminary experiment since they vary according to the nature of the reactants employed.

In general the temperature employed and the time of reaction are the factors which it is most important to watch. As to whether a monoor dienol ester is obtained is admittedly relatively difficult to determine due solely to the nature of the compounds in question. The elemental analysis will provide a good guide and in addition one can of course determine the percentage of groups R in the product.

In one method of operation, the 11:20-diketone is heated with an acid anhydride in the presence of a small amount of p-toluene sulphonic acid. The reaction is preferably carried out under reflux at a temperature between and 160, and the mixture is allowed to distill slowly to remove the acid formed. Although it is not essential, it is preferable, where the anhydride is a liquid, in order to obtain a more exact control, to keep the volume of the reaction mixture constant by the addition of extra amounts of acid anhydride to compensate for the loss by distillation.

Since too vigorous conditions lead to the formation of a dienol ester, it is necessary to regulate carefully both the period of heating and the quantity of p-toluene sulphonic acid used, and consequently the optimum conditions must be determined by experiment in each case. It is preferable to use a quantity of p-toluene sulphonic acid equal to A of the weight of the sterol and to carry the reaction out for a period of 1 /2 hours at a temperature of This type of reaction may perhaps more conveniently be effected by the use of perchloric acid as the enolising agent, as in the process according to the invention, since with this substance there is less tendency to form the dienolesters. In this modification of the process the diketone' dissolved in the acid anhydride is treated with a perchloric acid and the mixture allowed to stand preferably at 0 for 2 hours. The course of the reaction may be followed conveniently by polarirnetric determinations since the enolisation is accompanied by a marked change in rotation. The length of time for carrying out the reaction is dependent on the amount of perchloric acid used and the. optimal conditions must be determined by experiment. The amount of perchloric acid is preferably limited to 01-20% of the weight of sterol, a convenient proportion being 10% and the temperature for the reaction is conveniently in the range of 20 to 50.

In order that the invention may be well understood, the following examples are given only as illustrations:

EXAMPLE 1 Preparation of 3fl:17a-dihydr0xy-11:20- diketoallopregnane Sfl-acetoxy-ll:ZO-diketoallopregnane (50 g.) in carbon tetrachloride (475 ml.) was added with slight cooling to a solution of perchloric acid (aqueous 50%; 1.0 ml.) in acetic anhydride (25 ml.), and the homogeneous solution allowed to stand at room temperature for 2 hours. The mixture was then washed twice with ice-cold 5% sodium hydroxide solution and twice with water, and the solvent distilled otf, finally under reduced pressure. The semi-crystalline residue was taken up in chloroform (100 ml.) and a solution of monoperphthalic acid in ether (2.8 N; 200 ml.) added. After 2 hours at room temperature, the mixture was washed twice with ice-cold 5% sodium hydroxide solution, twice with water, and the solvents removed under reduced pressure. A hot solution of potassium hydroxide in 95% methanol (0.8 N; 400 ml.) was added to the gummy residue, and the mixture refluxed vigorously for a few minutes, when crystalline material started to separate out and the mixture quickly became solid. It was then cooled rapidly to room temperature, and water (2.1) added. The suspended solid was filtered off and dried in vacuo at 60 to give 313: 17adihydoxy 11:20 diketoallopregnane as a white solid. Wt.=42.2 g. (91% from 3fi-acetoxy-11:20-diketoallopregnane) M. P. 267270 and 289291.

EXAMPLE 2 General methods (a) H0mogene0us.--A solution of perchloric acid (50% aqueous; 0.1 ml.) in acetic anhydride (5 ml.) was added at room temperature to a solution of 3 fi-acetoxy- 11 :ZO-diketoallopregnane (5.0 g.) in the solvent (45 ml.), and the homogeneous solution allowed to stand at room temperature (see table for times required for various solvents.) Ether was then added, the mixture washed twice with ice-cold sodium hydroxide, twice with water, dried over anhydrous magnesium sulphate, and the solvent evaporated, finally in vacuo. The crude residue was taken up in chloroform ml.) and an ethereal solution of monoperphthalic acid (2.8 N; ml.) added. After two hours at room temperature, more ether was added, the mixture washed twice with ice-cold 5% sodium hydroxide solution, twice with water, and the organic layer dried over magnesium sulphate. After removal of the solvent, finally in vacuo, the residue was warmed on a steam bath, and a solution of potassium hydroxide in 95% methanol (0.8 N; 40 ml.) (previously heated to the boiling point) was added all at once, the flask being rapidly swirled round during the addition. The mixture was heated on a steam bath for a few minutes until all the material had gone into solution. On cooling, crystalline material immediately started to separate out, and the mixture was then cooled rapidly to room temperature. Water was added, the solid filtered oif, washed with water until the washings were neutral, followed by acetone (2 x 10 ml.), and dried in vacuo giving 3 133170:- dihydroxy-ll:ZO-diketoallopregnane, M. P. 265-8 and 286-90". (See table for yields.) [a] +65 (dioxan).

(b) Heter0gene0us.-A solution of perchloric acid (50% aqueous; 0.1 ml.) in acetic anhydride (5 ml.) was mixed with a solution or suspension of 3 fi-acetoxy11:20- diketoallopregnane (5.0 g.) in the solvent (125 ml.), and the mixture shaken or efiiciently stirred at room temperature. Ether was then added, and the mixture washed twice with ice-cold 5% sodium hydroxide solution, twice with water, dried over magnesium sulphate, and the solvents removed, finally in vacuo. The subsequent procedure was then identical with that described for the homogeneous reaction.

EXAMPLE 3 The following table shows the results obtained by means of the above procedures using various solvents.

TABLE Approx. Homo- 33 5 3 dlelecgeneous Time Catalyst Solvent tric or hours dr'ox hetero' dikelioallostant geneous pregnane Perchloric aeid. Acetic an- 20. 5 homoge- 2% 67 hydride. neous. Do Carbon 2.3 .do 1 92 tetrachloride. Do Trichloro- 3. 4 .do 1 85 e t; h yl one. Do Benzene 2. 3 d0 1% 80 Do Chloro- 5.0 do 1% 77 form. Do Methyl- 6.5 do- 2% 73 one chloride. Do n-Hexane- 1. 87 hetero- 5 73 geneous.

We claim:

1. A process for the monoenolesterification at the 20- position of an allosteroid compound having the general formula where R is a group selected from the group consisting of a hydroxy group, an acyloxy derived from a lower alkyl carboxylic acid and a benzoyloxy group which comprises reacting said compound with an aliphatic carboxylic acid anhydride containing from 4-10 carbon atoms in the presence of perchloric acid and a solvent medium for said allosteroid compound.

2. A process for the monoenolacetylation of 3-acetoxy- 11:20-diketoallopregnane at the 20-position which comprises reacting said compound with acetic anhydride in the presence of perchloric acid and an organic solvent medium for said compound having a dielectric constant substantially less than the dielectric constant of acetic anhydride and which is unable to act as a Lewis base for acylium ions.

3. The process defined in claim 2 in which said solvent medium comprises a halogenated hydrocarbon.

4. A process for the monoenolacetylation of 3-acetoxylizzo-diketoallopregnane at the 20-position which comprises reacting said compound with acetic anhydride in the presence of perchloric acid and a solvent medium including from 50-95% of carbon tetrachloride.

5. A process for the monoenolesterification at the 20- position of an allosteroid compound having the general formula where R is a group selected from the group consisting of a hydroxy group, an acyloxy derived from a lower alkyl carboxylic acid and a benzoyloxy group, which comprises reacting said compound with an aliphatic carboxylic acid anhydride containing from 4-10 carbon atoms in the presence of perchloric acid and a solvent medium which comprises a solvent which has a dielectric constant substantially less than that of said carboxylic acid anhydride and is unable to act as a Lewis base for acylium ions.

6. The process of claim 5 in which the solvent medium comprises a halogenated hydrocarbon.

7. The process of claim 6 in which said halogenated hydrocarbon is carbon tetrachloride.

8. The process of claim 5 in which the quantity of perchloric acid present is from 0.1-20% by weight of said starting compound.

9. The process of claim 5 in which the said solvent represents 50-95% of the total solvent medium.

Marshall et al.: JACS 70, 1837-39 (1948). Kritchevsky: JACS 74, 483-86 (1952). 

1. A PROCESS FOR THE MONOENOLESTERIFICATION AT THE 20POSITION OF AN ALLOSTEROID COMPOUND HAVING THE GENERAL FORMULA 